In this paper, we demonstrate the strong influence of the regioregularity (RR) of poly(3-hexylthiophene) (P3HT) on the optical anisotropy of hybrid P3HT/fullerene films before and after thermal annealing. We determined the conversion efficiency and characterized the optical anisotropy of P3HT/6,6-phenyl-C61-butyric acid methyl ester (PCBM) blends featuring various values of RR. Unlike grazing-incidence X-ray diffraction analysis, optical anisotropic measurement provides a clear and convenient view of the polymer orientation and the device anisotropic absorption at the same time. By calculating the in-plane and out-of-plane optical constants (extinction coefficients and refractive indices), we determined that the optical anisotropy of P3HT/PCBM films was improved in both orientations upon increasing the RR. Upon increasing the thermal annealing temperature, the main chains of high-RR P3HT were converted from an amorphous structure to an alignment parallel to the substrate, resulting in higher optical anisotropy. The degree of anisotropy of the high-RR P3HT/PCBM blend was up to six times higher than that of the low-RR sample. This strong RR effect on optical anisotropy was also evident in the power conversion efficiency of large-area P3HT/PCBM-based organic solar cells.